Association of anti-TNF with decreased survival in steroid refractory ipilimumab and anti-PD1 treated patients in the Dutch Melanoma Treatment Registry

Background Unleashing the immune system by PD-1 and/or CTLA-4 blockade can cause severe immune-related toxicity necessitating immunosuppressive treatment. Whether immunosuppression for toxicity impacts survival is largely unknown. Patients and methods Using data from the prospective nationwide Dutch Melanoma Treatment Registry (DMTR), we analysed the association between severe toxicity and overall survival (OS) in 1250 patients with advanced melanoma who were treated with immune checkpoint inhibitors (ICI) in first line between 2012 and 2017. Furthermore, we analysed whether toxicity management affected survival in these patients. Results 1250 patients were included, of whom 589 received anti-PD1 monotherapy, 576 ipilimumab and 85 combination therapy. 312 patients (25%) developed severe (grade ≥3) toxicity. Patients experiencing severe ICI toxicity had a significantly prolonged survival with a median OS of 23 months compared to 15 months for patients without severe toxicity (HRadj 0.77; 95%CI 0.63-0.93). Among patients experiencing severe toxicity, survival was significantly decreased in patients who received anti-TNF +/- steroids for steroid-refractory toxicity compared to patients who were managed with steroids only (HRadj 1.61; 95%CI 1.03-2.51), with a median OS of 17 months and 27 months, respectively. Conclusion Patients experiencing severe ICI toxicity have a prolonged overall survival. However, this survival advantage is abrogated when anti-TNF is administered for steroid-refractory toxicity. Further prospective studies are needed to assess the effect of different immunosuppressive regimens on checkpoint inhibitor efficacy.